Iron and vitamin D deficiency in preterm babies - a potential programming link to cardiovascular disease in later life

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1 Note: for non-commercial purposes only Iron and vitamin D deficiency in preterm babies - a potential programming link to cardiovascular disease in later life Conlon C.A. 1, Cormack B.E. 2,3,4, Moor C.F. 1, Emmett B.K. 1, von Hurst P.R. 1, Mugridge O.A. 1, Bloomfield F.H. 2,3,4 1 Massey University, College of Health, Nutrition and Dietetics, Auckland, New Zealand, 2 Newborn Services, Auckland City Hospital, Auckland District Health Board, Auckland, New Zealand, 3 Liggins Institute, The University of Auckland, Auckland, New Zealand, 4 Gravida: National Centre for Growth and Development, Auckland, New Zealand

2 Study location

3 Study location

4 Iron and vitamin D deficiency Reduced accretion, increased requirements for postnatal growth, excessive losses and lack of sun exposure. Deficiency states are associated with an array of issues for the preterm infant including impaired neurodevelopment, immune dysfunction and bone development. Also increased risk of iron overload due to immature regulatory mechanisms Can lead to impaired neurodevelopment

5 Beyond neurodevelopment & bone health Preterm birth has been associated with increased risk of cardiovascular disease (CVD) in later life. It has been hypothesised that common micronutrient deficiencies in early life may contribute to CVD risk in preterm babies. Experimental data suggest that iron and vitamin D deficiency may alter development of the heart, vasculature and metabolic pathways resulting in altered function, thereby potentially leading to cardiovascular disease.

6 Article Fetal anemia leads to augmented contractile response to hypoxic stress in adulthood. Craig S Broberg, George D Giraud, Jess M Schultz, Kent L Thornburg, A Roger Hohimer, Lowell E Davis Division of Maternal-Fetal Medicine, Medical Research Bldg., L-458, 3181 SW Sam Jackson Park Rd., Portland, OR , USA. AJP Regulatory Integrative and Comparative Physiology (Impact Factor: 3.28). 10/2003; 285(3):R DOI: /ajpregu Source: PubMed ABSTRACT In response to chronic fetal anemia, coronary blood flow, maximal coronary conductance, and coronary reserve increase. We sought to determine whether chronic fetal anemia alters left ventricular (LV) function in adulthood. We studied adult sheep that had been made anemic for 20 days in utero by phlebotomy. They were transfused just before birth. At 7 mo of age, LV function was measured by pressure-volume loops at rest and during hypoxic stress. The in utero anemia group (n = 8) did not differ from controls (n = 5) with respect to hematocrit, heart and body weight, or baseline hemodynamic parameters. However, the effect of hypoxia (relative to baseline) on multiple indexes of systolic function was different between the two groups. End-systolic elastance increased in the in utero anemia group (baseline to hypoxia) by / mmhg/ml (mean +/- SD) but changed little in controls (0.24 +/- 0.45), which shows that the response to hypoxia was significantly different (P < 0.01) between groups. Similarly, the maximum derivative of LV pressure with respect to time increased in the in utero anemia group (486 +/- 340 mmhg/s,) but on average fell in the controls (-503 +/- 211 mmhg/s) with the response again being significantly different (P < 0.03). We conclude that in sheep, perinatal anemia can alter cardiac responses to hypoxic stress in the adult long after restoration of normocythemia. In sheep, fetal anaemia alters coronary conductance and increases susceptibility to ischaemia-reperfusion injury in adulthood. This study demonstrates that anaemia in utero at an equivalent gestational age as preterm babies may be associated with altered cardiac development.

7 These findings provide the first evidence in humans that fetal anaemia is associated with an increased cardiovascular risk profile in adulthood.

8 Vit D deficient, young male and female offspring have elevated mean arterial pressure (MAP) and heart rate (HR) and endothelial vasodilator dysfunction

9 Aim The aim of this study was to determine the iron and vitamin D status of preterm babies after hospital discharge.

10 Routine supplementation LBW <2500g VLBW <1500g ELBW <1000g On NICU at Auckland only preterm infants <32w and/or <1800g routinely receive 3-6mg/kg/d iron and vitamin D supplements ( IU per day) unless clinically indicated

11 Methods Situational analysis. Babies (< 37 weeks gestation) were recruited to the study 4 months after discharge through NICU at Auckland City Hospital. At four months after discharge measured infant haemoglobin (<110g/L), serum ferritin (<12µg/L) and soluble transferrin receptor (>2.4mg/L), C-reactive protein and serum 25-hydroxyvitamin D (25(OH)D) concentrations (insufficiency 50nmol/L). Anthropometric measures: weight, length and head circumference were measured. Information about supplementation and mode of feeding was collected.

12 Study design Contact details retrieved for 208 potential participants from NICU log book 128 Parents could not be contacted 24 Parents declined 2 infants excluded 1 still in NICU 1 located outside of Auckland region 80 Parents Contacted 56 Parents consented Infants; n=73 4 parents could not be contacted to make an appointment 18 Infants excluded because 25(OH)D biomarkers not available 6 Infants excluded iron biomarkers not available Eligible Participants n=67 (17 sets of twins) Final n=61 for iron results n=48 for 25(OH)D

Characteristics of the babies according to receiving or not receiving iron supplements Gender n (%) Characteristics Males Females Gestational Age (weeks+days) Median [25 th, 75 th percentile] 32

13 Characteristics of the babies according to receiving or not receiving iron supplements Gender n (%) Characteristics Males Females Gestational Age (weeks+days) Median [25 th, 75 th percentile] 32 weeks n (%) >32 weeks n (%) Birth Weight (kg) Infant Ethnicity n (%) Mean±SD 1.8kg n (%) >1.8kg n (%) European Maori Pacific Island Asian Indian Singleton Birth n (%) Twin n (%) Infants who received supplements after discharge n= (40) 18 (60) 32+5 [30+0, 34+3] 14 (46.7) 16 (53.3) 1.58± (76.7) 7 (23.3) 17 (56.7) 5 (16.7) 1 (3.33) 3 (10.0) 4 (13.3) 15 (50) 15 (50) Infants who did not receive supplements after discharge n= 31 P value 23 (74.2) 8 (25.8) 0.007* 35+3 [34+3, 36+5] 0 (0) 31 (100) 2.54± (0) 31 (100) 17 (54.8) 3 (9.68) 5 (16.1) 5 (16.1) 1 (3.23) <0.001** <0.001* <0.001** <0.001* 13 (41.9) 18 (58.1) 0.53

14 Results Incidence of Iron Deficiency and Iron Deficiency Anaemia in Preterm Infants at Four Months after Discharge Iron Deficiency Anaemia a Iron Deficiency b Optimal Iron Status c Iron Overload d n (%) 10 (16.4) 4 (6.6) 47 (77.0) 0 (0) a Defined as haemoglobin <110 g/l, serum ferritin <12 µg/l and/or stfr>2.4 mg/l; b Defined as haemoglobin >110 g/l, serum ferritin <12 µg/l and/or stfr>2.4 mg/l; c Defined as haemoglobin>110 g/l, serum ferritin >12 µg/l and stfr<2.4 mg/l; d Defined as serum ferritin >300 µg/l

15 Characteristics of Preterm Infants with Suboptimal Iron Status at Four Months after Discharge Characteristics Optimal Iron Status Suboptimal Iron Status P value Incidence n (%) 47 (77.0) 14 (23.0) - Gestational Age 32 weeks n (%) >32 weeks n (%) 14 (100) 33 (70.2) 0 (0) 14 (29.8) 0.026* Birth Weight 1.8kg n (%) >1.8kg n (%) Received Iron Supplements Yes n (%) No n (%) 20 (87) 27 (71.2) 27 (90) 20 (64.5) 3 (13) 11 (28.8) (10) 11 (35.5) 0.018**

16 Characteristics of the babies according to receiving or not receiving vitamin D supplements Gender n (%) Gestational Age Characteristics Males Females 32 weeks n (%) >32 weeks n (%) Infants who received supplements after discharge n= 25 8 (32) 17 (68) 11 (44) 14 (56) Infants who did not receive supplements after discharge n= (78.3) 5 (21.7) 0 (0) 23 (100) P value <0.001** <0.001* Birth Weight (kg) Mean±SD 1.8kg n (%) >1.8kg n (%) 1.5± (76) 6 (24) 2.5± (9.5) 21 (90.5) <0.001** <0.001* Infant Ethnicity n (%) European Maori Pacific Island Asian Indian 11 (44) 2 (8) 2 (8) 4 (10.0) 4 (13.3) 13 (56.5) 1 (4.3) 4 (17.5) 1 (4.3) 2 (8.7) Singleton Birth n (%) Twin n (%) 13 (52) 12 (48) 11 (47.8) 12 (52.2) 0.53

17 Feeding Type With or Without Vitamin D Supplements, by Serum 25(OH)D Concentrations in Preterm Infants * *Ŧ *Ŧ n=13 * n=12 n=9 n=14 <0.008 = level of significance, n=number *P=0.0001; Exclusive breastfeeding without Vitamin D supplements versus exclusive breastfeeding with Vitamin D supplements, formula fed without Vitamin D supplements and formula fed with Vitamin D supplements ŦP=0.002; Formula fed with Vitamin D versus formula fed without Vitamin D

18 Conclusion We conclude that suboptimal micronutrient status in preterm babies 4 months after hospital discharge may be common in babies who don t receive routine supplementation.

19 Interpretation Optimising nutrition after discharge as well as in hospital may ameliorate the potential cardiovascular disease burden in survivors of preterm birth, a population that is increasing steadily worldwide

20 Thank you Charlotte Moor, Barbara Cormack, Briar Emmett, Owen Mugridge & Professor Frank Bloomfield. To all the babies and families who took part in the study

Vitamin D & Iron Dosing Guidelines

Vitamin D & Iron Dosing Guidelines Ayman Khmour, MD I have no actual or potential conflict of interest in relation to this program. Objectives Review Ca metabolism Review Recent AAP Guidelines Review CMH